New treatment promising for Parkinson's

NEW YORK -- An experimental treatment for Parkinson's disease seemed to improve symptoms - dramatically so, for one 59-year-old man - without causing side effects in an early study of a dozen patients.

The gene therapy treatment involved slipping billions of copies of a gene into the brain to calm overactive brain circuitry.

The small study focused on testing the safety of the procedure rather than its effectiveness, and experts cautioned it's too soon to draw conclusions about how well it works. But they called the results promising and said the approach merits further studies.

"We still have quite a bit more testing to do," said Dr. Michael Kaplitt of Weill Cornell Medical College in New York, an author of the study. Still, "the initial results are extremely encouraging."

Kaplitt and collaborators report their results in this week's issue of the British medical journal, The Lancet.

They're not alone in trying gene therapy for Parkinson's. In April, another team told a medical meeting that its experiments, which delivered a different kind of gene to a different part of the brain, also appeared safe and gave a preliminary hint of benefit.

More than half a million Americans have Parkinson's. They endure symptoms that include tremors, rigidity in their limbs, slowness of movement and impaired balance and coordination. Eventually they can become severely disabled.

Nathan Klein, a 59-year-old freelance television producer in Port Washington, N.Y., said the disease left him "pretty messed up." It weakened his voice, impaired his walking and made his hand tremble so badly he couldn't hold a glass of wine without spilling it all.

Klein was the first patient to be treated with Kaplitt's gene therapy procedure in 2003, and he said his symptoms gradually subsided afterward. Nowadays, he said, apart from freezing now and then when he wants to walk, the symptoms are basically gone.

"I'm elated," said Klein, who continues to take his regular pills for the disease. "It's unbelievable."

Kaplitt, who has a financial interest in Neurologix Inc., which paid for the research, noted that the 12 patients in the study still have Parkinson's symptoms. The amount of medication they were already taking for their symptoms didn't change significantly in the year after the surgery.

Current medicines can control symptoms, but can't stop the disease from getting worse over time, and they can produce troublesome side effects like uncontrollable movement.

Some patients gain relief from a surgical treatment called deep brain stimulation, in which electrodes are placed in the brain and connected to a programmable stimulator.

Kaplitt's procedure was aimed at achieving the same goal as that surgery, calming overactive circuitry in the brain. It gets overactive because it loses the normal supply of a chemical called GABA. The gene therapy was designed to make the brain produce more GABA.

For the gene therapy surgery, a tube about the width of a hair was threaded through a hole about the size of a quarter at the top of the skull. The tube delivered a dose of a virus engineered to ferry copies of a gene into cells of a brain region called the subthalamic nucleus. The gene copies enable the cells to pump out more GABA.

The Lancet paper reports that over a year, patients showed no side effects from the procedure. What's more, they showed improvements in an overall assessment of symptoms like tremors, stiffness and walking problems.

The improvements were evident at a checkup three months after the procedure and persisted to the end of the study, one year after the surgery, researchers reported. By that time, the overall amount of improvement from before surgery was about 24 percent when measured at times that patients were off their normal medication, and 27 percent at times when they were on medication.

Most of the effect appeared on just one side of the body. Because of concerns about safety with the untested procedure, the researchers treated only the brain circuitry controlling one side of the body.

Dr. Karl Kieburtz of the University of Rochester Medical Center, who didn't participate in Kaplitt's work, said the lack of any apparent side effects is itself significant.

But he urged caution in interpreting the evidence of benefits in symptoms. Other experimental therapies that looked good at such a preliminary stage have failed to pan out in more rigorous studies, he said, so more research is needed.

Future studies could include a head-to-head test against deep brain stimulation to see which relieves symptoms better, said neurosurgeon Dr. Guy M. McKhann of the Columbia University Medical Center in New York.

Dr. J. Timothy Greenamyre of the University of Pittsburgh, who was also familiar with the results, said the new study and prior research in animals leave him "very optimistic" about Kaplitt's approach.

Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial

Summary

Background

Dopaminergic neuronal loss in Parkinson's disease leads to changes in the circuitry of the basal ganglia, such as decreased inhibitory GABAergic input to the subthalamic nucleus. We aimed to measure the safety, tolerability, and potential efficacy of transfer of glutamic acid decarboxylase (GAD) gene with adeno-associated virus (AAV) into the subthalamic nucleus of patients with Parkinson's disease.

Methods

We did an open label, safety and tolerability trial of unilateral subthalamic viral vector (AAV-GAD) injection in 11 men and 1 woman with Parkinson's disease (mean age 58·2, SD=5·7 years). Four patients received low-dose, four medium-dose, and four high-dose AAV-GAD at New York Presbyterian Hospital. Inclusion criteria consisted of Hoehn and Yahr stage 3 or greater, motor fluctuations with substantial off time, and age 70 years or less. Patients were assessed clinically both off and on medication at baseline and after 1, 3, 6, and 12 months at North Shore Hospital. Efficacy measures included the Unified Parkinson's Disease Rating Scale (UPDRS), scales of activities of daily living (ADL), neuropsychological testing, and PET imaging with 18F-fluorodeoxyglucose. The trial is registered with the ClinicalTrials.gov registry, number NCT00195143.

Findings

All patients who enrolled had surgery, and there were no dropouts or patients lost to follow-up. There were no adverse events related to gene therapy. Significant improvements in motor UPDRS scores (p=0·0015), predominantly on the side of the body that was contralateral to surgery, were seen 3 months after gene therapy and persisted up to 12 months. PET scans revealed a substantial reduction in thalamic metabolism that was restricted to the treated hemisphere, and a correlation between clinical motor scores and brain metabolism in the supplementary motor area.

Interpretation

AAV-GAD gene therapy of the subthalamic nucleus is safe and well tolerated by patients with advanced Parkinson's disease, suggesting that in-vivo gene therapy in the adult brain might be safe for various neurodegenerative diseases.

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